The present invention relates to an advantageous process for the preparation of 2,6-dichloro-5-fluoronicotinonitrile starting from 3-cyano-2-hydroxy-5-fluoropyrid-6-one and/or its tautomers and/or its salts and/or tautomers thereof, and to 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt and tautomers thereof (called 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt in the following).
2,6-dichloro-5-fluoronicotinonitrile is the starting compound for synthesis of important units for antibiotics from the class of so-called "aza"-analogous quinolones (cf., for example, German Offenlegungsschrift 35 14 076). Such a use also requires preparation processes for the intermediate products which give the intermediate products in a high purity, high yield and high economic efficiency.
Some preparation processes for 2,6-dichloro-5-fluoronicotinonitrile are already known. Thus, 2,6-dichloro-5-fluoronicotinonitrile can be prepared starting from 2,6-dichloro-5-fluoro-3-trichloromethylpyridine by reaction with ammonium chloride and copper oxide in sulfolane at 180 to 190.degree. C. (cf., for example, WO 95 26 340). However, the large amount of hydrochloric acid formed and the large amounts of solid to be handled are a great disadvantage for industrial realizations.
2,6-dichloro-5-fluoronicotinonitrile can furthermore be obtained from 2,6-dihydroxy-5-fluoronicotinonitrile by reaction with phosphorus pentachloride in phosphorus oxychloride (cf., for example, EP-A 333 020). If 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt, which is not yet known in the literature, is reacted under the conditions described in EP-A 333 020, the desired product is obtained in a yield of only 67% at a purity of 72.6% (cf. Example 2).
Reworking of the process described in EP-A 333 020 moreover shows a decisive disadvantage that if 2.25 equivalents of phosphorus pentachloride, based on the hydroxyl functions to be chlorinated, are used, relatively large amounts of more highly chlorinated by-products are formed, in addition to the desired product 2,6-dichloro-5-fluoronicotinonitrile.
The use of phosphorus pentachloride, which, as a solid, in large amounts, can be handled only with great difficulty and with a very high expenditure on safety, furthermore presents extreme problems, and the hydrolysis necessary for working up is made difficult due to the high residual content of phosphorus pentachloride and the production of relatively large amounts of phosphorus-containing waste waters.
For chlorination of analogous dihydroxynicotinonitriles, the sole use of phosphorus pentachloride (cf., for example, Chem. Pharm. Bull. 35 2280-2285 (1987)) is described, which presents great problems industrially for the abovementioned reasons. For this purpose, the sole use of phosphorus oxychloride as a solvent and chlorinating agent is also described (cf., for example, German Offenlegungsschrift 23 07 444) as well as an addition of large amounts (163 mol %) of triethylamine (cf., for example, Angew. Chem. 92, 390 (1980)).
The reaction of 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt exclusively with phosphorus oxychloride (as a solvent and chlorinating agent) leads to no reaction. Even at elevated temperature, phosphorus oxychloride is not sufficiently reactive. 2,6-dichloro-5-fluoronicotinonitrile is to be detected in the product isolated only in traces, and the addition of triethylamine also does not lead to a noticeable reaction. In the system of phosphorus oxychloride/triethylamine/reduced amounts of phosphorus pentachloride (1.15 equivalents per function to be chlorinated), low yields and a higher proportion of undesirable by-products are again observed (cf. Example 3).
There is therefore still a need for a process for the preparation of 2,6-dichloro-5-fluoronicotinonitrile which can readily be carried out industrially, gives the product with good yields and in good purities and is economically advantageous.